Gulf War Veterans' Illnesses (GWVI), a term encompassing an array of chronic and unexplained disease symptoms, is characterized by higher rates of gastrointestinal disorders in Veterans that served in the Gulf War compared to their non-deployed counterparts. Our previous work and work by others have identified a protective role for IL-17 and IL-17C in the intestinal epithelium with likely roles in protecting the barrier and halting the development of irritable bowel syndrome (IBS). The loss of IL-17 or IL-17C results in susceptibility to inflammation-based models of gastrointestinal distress. Moreover, the targets of both IL-17 and IL-17C include intestinal epithelial cells (IECs) and IL-17 cytokine-mediated effects include positively regulating IEC permeability, antimicrobial peptide (AMP) expression, and microbial colonization in the GI tract. Furthermore, stress, including posttraumatic stress disorder (PTSD), has been shown to exacerbate IBS. Since GWVI patients suffer higher rates of both PTSD and IBS compared to their non-deployed counterparts, IL-17 family cytokine expression may be linked to both conditions. Hence, we will be investigating such IEC-dependent mechanisms in the context of GWVI, stress, and IBS to determine if aberrant IL-17 or IL-17C signaling can explain GWVI-associated IBS. We additionally will be performing experiments to determine if either cytokine has a therapeutic value in restoring deleterious epithelial functions and improving IBS symptoms. Finally, we will be analyzing these mechanisms in a GWVI mouse model in a pilot study to determine if trends in such parameters exist, which will be the basis for future large-scale clinical studies. Overall, our proposal aims to identify novel disease mechanisms as well as new therapeutic options for the treatment of gastrointestinal disorders in GWVI patients.